Patients with pancreatic cancer (PC) have a median survival of only 6 months and a five-year survival of less than 5%, hence making PC one of the deadliest cancer (Klein et al., 2013, Nat. Rev. Cancer 13:66-74; Howlander et al., SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations) Online Data—http://seer.cancer.gov/csr/1975_2009_pops09/index.html). Severity of PC is due to its identification at late stages, rapid local invasion, early metastases, and meager response to current chemotherapeutic agents. Current therapies result in minimal survival advantage and are linked with multiple adverse events and drug resistance. Hence, there is an urgent need for novel agents which are less toxic and offer greater benefits over conventional therapy.
Pancreatic ductal adenocarcinoma comprises greater than 90% of PC (Samuel and Hudson, 2012, Nat. Rev. Gastroenterol. Hepatol. 9:77-87). Poor prognosis and disease stage at diagnosis contributes to low survival rate (Iovanna et al., 2012, Frontiers in Oncology:2). Chemotherapy remains the current standard of care for advanced PC patients, which include gemcitabine alone or in combination with erlotinib or a highly toxic regimen FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) (Klein et al., 2013, Nat. Rev. Cancer 13:66-74; Moore et al., 2007, J. Clin. Oncol. 25:1960-1966). The current standard of care only improves survival rate on average by 6 months, but is associated with poor quality of life due to high toxicity. Molecular and cellular heterogeneity of PC tumors contribute to resistance to current standard of chemotherapy (Samuel and Hudson, 2012, Nat. Rev. Gastroenterol. Hepatol. 9:77-87). Therefore, there is an urgent need to develop novel approaches to battle metastatic PC.
Many signaling pathways have been suggested to be associated with chemo-resistance, including NF-κB, PI3k-Akt and NOTCH pathways in cancer, (Zhou et al., 2014, AAPS J. 16:246-257; Long et al., 2011, Expert Opin. Ther. Targets 15:817-818; Arlt et al., 2003, Oncogene 22:3243-3251; Wang et al., Nat. Rev. Gastroenterol. Hepatol. 8:27-33); however, chemo-resistance in PC has mainly been associated with aberrant activation of the NF-κB pathway (Arlt et al., 2012, Oncogenesis 1:e35). Further, the NF-κB pathway has been known to be induced in presence of chemotherapeutic drugs as well as radiation in PC cells 9 Arlt et al., 2003, Oncogene 22:3243-3251; Brach et al., 1991, J. Clin. Invest. 88:691-695; Bharti and Aggarwal, 2002, Biochem. Pharmacol. 64:883-888), hence making this pathway one of the hot targets for combinational treatments with current drugs in the clinic (Arlt et al., 2012, Oncogenesis 1:e35; Carbone and Melisi, Expert Opin. Ther. Targets 16 Suppl. 2:S1-S10; Ullenhag et al., 2015, PLoS One 10:e03121197; Infante et al., 2011, Eur. J. Cancer 47:199-205). The mammalian transcription factor NF-κB is formed by homo- or hetero-protein dimer complex of Rel-family proteins (Gilmore, 2006, Oncogene 25:6680-6684). The most abundant form of NF-κB exists in the form of heterodimer consisting of RelA (also known as p65) and p50 complex. The RelA and p50 NF-κB complex is inhibited in the cytoplasm from entering the nucleus by inhibitor of κB proteins (IκBα). In classical activation of NF-κB pathway, upon inflammatory stimuli (like TNF-α), downstream IκB kinase complex (IKK), which is made up of two catalytic kinases (IKKα and IKKβ) and a regulatory component IKKγ, is activated via phosphorylation (Gilmore, 2006, Oncogene 25:6680-6684). Upon activation of IKK, IKK phosphorylates IκBα. Phosphorylated IκBα is polyubiquitnated and degraded, hence RelA and p50 complex can freely localize to the nucleus and interact with their corresponding gene targets. Upon activation, NF-κB upregulates the transcription of anti-apoptotic proteins (like Blc-2, Bcl-xL, Mcl-1, etc), proliferative proteins (cyclin D), proteins involved in cell invasion (VEGF, MMPS, etc.) and pro-inflammatory cytokines (TNF-α, and different interleukins) (Gilmore, 2006, Oncogene 25:6680-6684).
Over the past decade, NSAIDs have emerged as potent chemopreventive agents (Streicher et al., 2014, Cancer Epidemiology Biomarkers & Prevention 23:1254-1263; Tan et al., Cancer Prev. Res. 4:1835-1841; Bonifazi et al., 2010, Eur. J. Cancer Prev. 19:352-354; Chan et al., 2007, Arch. Intern. Med. 167:562-572; Agrawal and Fentiman, 2008, Int. J. Clin. Pract 62:444-449; Johannesdottir et al., 2012, Cancer 118:4768-4776; Seshasi et al., 2012, Arc. Intern. Med. 172:209-216; Trabert et al., 2014, J. natl. Cancer Inst. 106:djt431). Out of all the NSAIDs, aspirin (ASA) has received more attention for its chemopreventive ability in different cancers, specifically colorectal cancer (Rothwell, 2013, Recent Results Cancer Res. 191:121-142; Drew et al., 2016, Nature Reviews Cancer; 16:173-186). Further, there have been different clinical trials showing ASA to be clinically effective in reducing PC growth Streicher et al., 2014, Cancer Epidemiology Biomarkers & Prevention 23:1254-1263; Tan et al., Cancer Prev. Res. 4:1835-1841; Bonifazi et al., 2010, Eur. J. Cancer Prev. 19:352-354). Recent clinical studies showed that high ASA decreased PC incidence (Cui et al., 2014, Pancreas 43:135-140), however high doses or long term usage of ASA are also related to gastrointestinal (GI) toxicity (Toruner, 2007, Anadolu Kardiyol Derg, 7 Suppl 2: 27-30; Yeomans et al., 2009, Curr. Med. Res. Opin. 25:2785-2793). Hence, efforts have been made by different research groups to optimize ASA structure for improving its potency and ultimately reducing its toxicities (Drew et al., 2016, Nature Reviews Cancer; 16:173-186; Huang et al., 2011, J. Med. Chem. 54:1356-1364; Plano et al., 2016, J. Med. Chem. 56:1946-1959; Fiorucci et al., 2007, Br. J. Pharmacol. 150:996-1002; Basudhar et al., 2013, J. Med. Chem. 56:7804-7820).
Interest in designing selenium containing small molecules intensified after the link between selenium and cancer prevention strengthened based on preclinical, epidemiological and clinical investigations (Plano et al., 2016, J. Med. Chem. 56:1946-1959; Chung et al., Cancer Prev. Res. 4:935-948; Lin et al., 2011, Eur. J. Cancer 47:1890-1907; Nguyen et al., 2011, Cancer Prev. Res. 4:248-258; Chintala et al., 2010, Cancer Chemother. Pharmacol. 66:899-911; Li et al., 2009, Breast Cancer Res. Treat. 118:33-43; Martins et al., 2013, Molecules 18:5251-5264; Qi et al., 2012, PLoS One 7:e31539; Sharma and Amin, Future Med. Chem. 5:163-174). In the recent literature, several new selenium compounds have been developed including several from our laboratories and many of them have shown promising cancer preventive and/or therapeutic activity (Plano et al., 2016, J. Med. Chem. 56:1946-1959; Sharma and Amin, Future Med. Chem. 5:163-174; Alcolea et al., 2016, Eur. J. Med. Chem. 113:134-44; Ding et al., 2014, Carbohydr. Polym. 109:28-34; Zeng et al., 2014, Chem. Asian J. 9:2295-2302; Sharma et al., 2008, J. Med. Chem. 51:7820-7826). The mechanisms by which selenium containing molecules inhibit cancer growth differ according to the structure of the overall compound (Jackson and Combs, 2008, Curr. Opin. Clin. Nutr. Metab. Care 11:718-726). The most commonly described mechanisms by which selenium compounds exerts their anti-cancer ability are: induction of reactive oxygen species (ROS) or quenching of ROS (Plano et al., 2016, J. Med. Chem. 56:1946-1959); inhibition of different pro-survival proteins (like Bcl-xL and Survivin); induction of apoptosis; inhibition of angiogenesis; modulation of AKT, COX, p38 and NF-κB-signaling pathways (Gowda et al., 2013, Mol. Cancer Ther. 12:3-15; Sanmartin et al., 2008, Mini Rev. Med. Chem. 8:1020-1031; Sanmartin et al., 2012, Int. J. Mol. Sci. 13:9649-9672; Hu et al., 2008, Clin. Cancer Res. 14:1150-1158; Abbas and Sakr, 2013, J. Physiol. Biochem. 69:527-537).
In normal cells, the major source of ROS is mitochondria (Ray et al., 2012, Cell Signal 24:981-990). ROS are very unstable and can damage DNA and proteins (Sabharwal and Schumacker, 2014, Nat. Rev. Cancer 14:709-721). Cancer cells show high basal ROS levels because of mitochondrial activity as compared to their normal counterparts (Sabharwal and Schumacker, 2014, Nat. Rev. Cancer 14:709-721). Hence, ROS inducing agents have been proposed to kill cancer cells selectively over normal cells by increasing the amount of ROS enough to tip the balance towards cancer cell death (Schumacker, 2006, Cancer Cell 10:175-176). Drawback of the ROS inducing agents is that the cancer cells also have up-regulation of stress pathways like NF-κB (Ahn et al., 2007, Curr. Mol. Med. 7:619-637), which can upregulate not only anti-apoptotic proteins but anti-oxidant enzymes which can counter act the increased ROS levels in cancer cells (Sabharwal and Schumacker, 2014, Nat. Rev. Cancer 14:709-721; Morgan and Liu, 2011, Cell Res. 21:103-115; Reuter et al., 2010, Free Radic. Biol. Med. 49:1603-1616; Trachootham et al., 2009, Nat. Rev. Drug Discov. 8:597-591; Holstrom and Finkel, 2014, Nat. Rev. Mol. Cell. Biol. 15:411-421) Hence, it has been proposed that compounds that have dual action of increasing ROS levels and further inhibiting the NF-κB resistance pathway may play a major role in killing the cancer cells (Reuter et al., 2010, Free Radic. Biol. Med. 49:1603-1616). Further, ASA derived molecules like NO-aspirin are known to induce ROS species in cancer cells (Tanaka et al., 2014, Cell Cycle 5:1669-1674), while selenium containing compounds can either be a pro-oxidant or anti-oxidant depending on the types of active metabolites formed (Plano et al., 2016, J. Med. Chem. 1946-1959).
p21 and p27 are markers activated in the presence of DNA damage or apoptosis (Gartel and Tyner, 2002, Mol. Cancer Ther. 1:639-649; Abbas and Dutta, 2009, Nat. Rev. Cancer 9:400-414; Kastan and Bartek, 2004, Nature 432:316-323). Literature reports suggest that histone deacetylase (HDAC) inhibitors can activate p21 and p27 expression (Yang and Seto; 2007, Oncogene, 26:5310-5318; Blagosklonny et al., 2002, Mol. Cancer Ther. 1:937-941; Takai et al., 2004, Cancer 101:2760-2770). ASA also has been known to induce expression of both proteins (Marra et al., 2000, Circulation 102:2124-2130; Dikshit, 2006, J. Biol. Chem. 281:29228-29235) and could increase histone acetylation to show its effects (Passcquale et al., 2015, Br. J. Pharmacol. 172:3548-3564).
It has been demonstrated that inflammation plays a major role in PC initiation, progression and metastasis (Takahashi et al, 2013, Semin. Immunopathol. 35:203-227; Steele et al., 2013, Br. J. Cancer 108:997-1003; Marusawa and Jenkins, 2014, Cancer Lett. 345:153-156). Nuclear factor κB (NF-κB) pathway, one of the major inflammatory pathway, is well known for its inflammatory response, cell proliferation, and resistance to apoptosis. NF-κB is a major stress related pathway, and one of the targets of NF-κB are anti-oxidant proteins (Chen et al., 2007, Cancer Res. 67:1472-1486; Sullivan and Graham, 2008, Curr. Pharm. Des. 14:1113-1123). It has been demonstrated that activation of NF-κB in PC is also responsible for resistance towards first line chemotherapeutic agent, gemcitabine, in PC. Studies have suggested that the cancer cells acquire resistance to gemcitabine through aberrant activation of NF-κB pathway. Patients who show resistance to gemcitabine, have high expression of NF-κB in their tumor sites, which is correlated with less survival rates (Voutsadakis, 2011, World J. Gastrointest. Oncol. 3:153-164; Dhilon et al., 2008, Clin. Cancer Res. 14:4491-4499; Wang et al., 1999, Clin. Cancer Res. 5:119-127).
Thus, there is a need in the art to identify novel compounds which are useful for the treatment of pancreatic cancer, in addition to other diseases and disorders, and do not cause deleterious side effects in the subject. The present invention fulfills this need.